Amine salts of 8-halotheophylline



AMINE SALTS F S-HALGTIEOPHYLLINE James M. Hoibert, Lookout Mountain, and Irvine W.

Grate, Chattanooga, Tennqassignors to The Chattanooga Medicine Company, Chattanooga, Tenn., a corporation of Tennessee N0 Drawing. Application August 8, 19 51,

Sen'alNo. 240,988 7 5Claims. rouse-2'53 The present invention relates to a pharmaceutical com pound having enhanced diuretic activity, and comprises a halotheophylline salt of organic amines having at least one primary amino group in the molecule.

We are aware that theophylline itself has previously 7 been combined with various amines'for the purpose of solubilizing the theophylline in diuretic compositions. Probably the most common derivative of this type is theophylline-ethylene diamine, known under the common name aminophylline.

We have now found that if the theophylline of this type of composition is replaced by a halotheophylline,

ited satesPa ent-once particularly 8-bromotheophylline, vand 8-chlorotheophylline, not only'is the solubilityof the theophylline com: position increased to a greater degree than occurs from the reaction between theophylline and the same amine compounds, but the resulting salt is far superior as a' diuretic compound to the previously known diuretic compounds containing theophylline.

The remarkably increased diuretic properties of the halotheophylline-amine salts of the present invention make them valuable therapeutic agents in the relief of premenstrual tension, a condition upon which previously severity of the discomfort is directlycommensurate with. the amount of fluid accumulated or pounds of Weight" gained. Women who gain from 3 /2 to 4 pounds during the week preceding the menses are almostincapacitated due to the severity of the symptoms from Water toxemia.

The compounds of the present invention are singularly" efiicient in the relief of the symptoms associated with pre-menstrual tension. Patients to whom the compositions of the present invention are administered approximately one week before the onset ofmenses rarely gain more than one and one-half pounds, and in many cases no weight gain whatsoever is observed. Furthermore, patients who are placed under treatment with the products of the present invention, even after they have gained weight, have a diuresis within a few hoursafter beginning treatment, resulting in the prompt relief of the symptoms. 7

One outstanding characteristic of therapeutic prod,- ucts of the present invention in the treatment of premenstrual tension is that in most patients they prevent water accumulation without diuresis if the treatment is started early enough so that the patients have no sympperiod.

. methyl) amino methane. 1 i Otheramino compoundsgthat can-be' used' lforthe purposes of. the present'invention are-thejalkylene .di-m aminessuch as "ethylene diamine, propyleneldiamine, and he ramethylene ,diamin'e. Inf-addition, the lower-lpoly'f- "alkylenejpolyamines, such as diethylenetriamine and itri-- ethylenetetramine, can also be; employed. Certain aralkyl amines are also within thescopeof the present invention. These are'the amines'iin which a primary molecule compounds such as i Anobjectof the'present invention is to provide a therapeutic; product comprising, a halotheophylline salt of. an organic amine for use in the relief of pre-menstrual tensionwithout the presenceof side reactions usually associated with the administration of theophylline.

. Another' obje ct of. the present'inventionisto provide 'r a compound capable ofIeiTeCting unlockingipitre ssin- 1 induced edema in human females. V M Another object. of the present invention is to provide a theophylline derivative having a high water; solubility and a high degree of diureticactivity. v 1 Still another object of the present invention is to pro? vide a; diuretic' composition of enhanced. 7 activity which.

I is capable not 'only of. releasing addedwaterbut previously retainedwatef from' hurrian body tissues;-

p The compositions of theTpresenti invention are pre-.. pared by reacting an 8-,halotheophylline, sucli as 8-bjrci'mo' theophylline or -8-chlorotheophylline, with an organic amine compound characterized by thepresence of a pri-.

mary amino group :(NH2) on a hydrocarbon chain. of

not more than 6 carbon atoms- The simplest compounds withinthe scope of'fthe' present inv'entionare *fthe halotheophylline derivatives of relatively short chain primary alkyl amines suchas methylarnine';ethylamine";

and :n-butylamine. Other amine compounds whose halotheophyllinederivatives are Withinithe scopeof the; invention are the. unsaturated aliphatic mono-amines such i as allylamine. Furthermore, ,the. primary, amino group in'the molecule need not be attached tea-straight chain hydrocarbon igroup as long as :the group -is. aliphatic. f "Thus, suitable derivatives are madefojr the purpose of y reacting cycloheirylamine --With- 1 the present invention 'b the halotheophylline.

.Other aminefeompounds which form uitable halotheophylline. derivativesare the' alkanol aminesl such as, .monoethanolamine, '2-amiho%2-rnethyll-propanol; 2-1 trir(hyd roxylamino-Z-rhethyl-i-3 propanediol, and

amino group appears in *a" hydrocarbonichain attached to {an aryl,nucleusp withjonly one aryl nucleus in the benzylaminefi and p-rnetho ry-benzylaminearejtypical of this type of com-,- I

. p pound. f-These aryl alkylfainines should-be differentiated from v strictly aromatic amines such as. aniline and ho n'o- "jlogue s of aniline in which the amino group. is attached jrdirectly to the benzene ring. The strictlyaromatic aminesare not particularly suited for the purposes of thisinvention.

The method to beusedfor the preparation ofthe salts of the "amines with {the ,halotheophyllin'e depends primarily upon the solubility characteristics of the amine Y compound'used. ,yif the amine is: solublein water, the theophylline derivativedissolved in an aqueous solution containing an excess of the' amine; If necessary,

a the solution maybe gentlyfwarmed to etfect'complete ,70 toms of water toxemia throughout their pre-menstrual dissolution. The resulting solution is then filtered and evaporated at reduced temperatures and pressuresuntill the salt combination beginsto crystallize. The solution is then cooled to promote separation of the salt and the resulting crystals are removed'by filtration, after which the material is dried in' a vacuum desiccator.

Alternately, .-tl 1e halotheophylline, ground to a fine I powder, may be mixed directly Withia liquid amine. If

the direct combination of the reactantsproduces a high I PatentedJune 21', 1955 s 3 temperature gradient, the amine may be diluted with a solvent such as methanol and added gradually with constant stirring to the halotheophylline. The solvent and the excess amine are then removed at reduced temperatures and pressures, leaving the halo-theophylline-amino salt as a dry solid.

Another method of preparation may be used, particularly where the amine is insoluble in water. In this case the amine is converted to the more water soluble amine hydrochloride by treatment with hydrochloric acid and then dissolved in water. The halotheophylline, in the form of its sodium salt, is then introduced in the proper molar proportions with vigorous stirring to obtain complete solution. The solution is then concentrated at reduced temperatures and pressures until crystallization begins. Next the solution is cooled and the halotheophylline-amine salt is removed by filtration and dried in a vacuum dessicator.

The following specific examples will illustrate several specific reaction procedures in preparing the compounds of the present invention:

Example 1.-8-chl0r0the0phyllirze methylamine Fifty cc. of a 40% methylamine solution were diluted with an equal volume of water. To this solution small portions of S-chlorotheophylline were added until a total of 21.5 grams (0.1 M) were added. The contents were thoroughly mixed after each addition of the solid chlorotheophylline, and complete solution resulted. This solution was filtered and the filtrate concentrated at reduced temperatures and pressures until crystallization began to occur. After cooling of the mixture, the crystals were removed and filtered in a vacuum filter. The product was dried overnight in a vacuum desiccator which contained calcium chloride. Analysis for chlorotheophylline indicated the composition of this salt to contain one mole of chlorotheophylline for every mole of methylamine. The structure of the resulting salt is as follows:

Example 2.8-brom0the0phylline ethylenediamine 120 cc. of ethyienediamine (95100%) were dissolved in 250 cc. of absolute methanol and added gradually with thorough mixing and occasional cooling to 259 g. (1.0 M) of S-bromotheophylline. A thick slurry resuited, and this slurry was heated on a water bath maintained at a temperature of 60 C. and at reduced pressure to remove alcohol and the excess amine. The resulting hard cake was broken up and ground to a fine powder. Analysis of this material showed a molar ratio of l to l for the halotheophylline and amine indicating that a true molecular compound had been formed. This fact was also substantiated by the fact that the salt had a relatively sharp melting point. The resulting salt has the following structure:

It is also within the scope of the present invention to react the Shale-theophylline and the amine in pro portions other than the 1 to 1 molar proportions employed in the above examples. Where, for example, a r'iiamine such as ethylenediamine is used, 2 moles of the halotheophylline to 1 mole of the diamine may be employed to produce a double salt of the halo theophylline and diamine compound.

It will also be appreciated that in the reaction given above the chlorotheophylline can be substituted for the bromotheophylline, and vice versa, with due regard to the'diiference in molecular weights between these compounds. Similarly, other amine compounds having solubility characteristics similar to the methylamine and the ethylenediamine of the examples can be reacted in the same manner.

In testing the compositions of the present invention for their diuretic action, the following procedure was used:

When rats are given tap Water perorally on the basis of 5 cc. of water per 100 g. of body weight of each rat, on the average of 100% of the water so given will be excreted as urine over a four-hour period. If, in addition to the water, the rats are each given subcutaneously /2 unit of pitressin, an anti-diuretic drug, only 42% of the water, on the average, will be excreted. in conducting this test, the drug to be tested is given in a dosage on the basis of 0.1 g. of the product per kilogram body weight of the rat and the product is added in this proportion to the water and pitressin. In this way, the anti-pitressin action of each of the various compounds is tested in terms of the percent of water re covery from the rats.

Table 1 illustrates some of the physical properties of the compounds of the present invention, as well as their diuretic activities determined in accordance with the foregoing procedure.

It should be noted that in some instances the halotheophylline derivative of the amine is apparently the only type of theophylline derivative which will react to form salts with that amine. For example, it was found that the cyclohexylamine and n-butylamine would not react with normal theophylline whereas the halo derivatives of the theophylline would readily react with the respective amines and form true salts.

The diuretic activity of the halotheophylline compounds was also compared in a series of tests with the diuretic activity of the straight theophylline compounds of the same amines. in the case of benzylamine, the straight theophylline derivative had a diuretic activity of 73. When the theophylline was substituted by bromotheophylline, and the corresponding bromotheophyllinebenzylamine salt prepared, the resulting compound had a diuretic activity of 102. Similarly, the theophylline salt of Z-amino-Z-methyl-l-propanol has a diuretic activity of 66 whereas the bromotheophylline 2-amino-2- methyl-l-propanol had a diuretic activity of 116. Under the same test conditions, theophylline-ethylenediamine has a diuretic activity of 75 Whereas the bromotheophylline. derivative of ethylenediamine has a diuretic activity of 118.

The diuretic activity of a compound, as measured by the above test, is a good indication of its etfectiveness in the relief of pre-menstrual tension among human females. The relief of pre-menstrual tension by the diuretic compounds of the present invention may be explained when it is appreciated that pre-menstrual tension is a symptom-complex related to abnormal water storage during the pre-menstrual period and is essentially a water toxemia. The intensity of these symptoms vary directly as the amount of water retained, and relief of the symptoms accompanies the diuresis.

It will be understood that modifications and variations may be effected without departing from the scope of the novel concepts of the present invention.

TABLE I Percent Percent V Approxi- Com mm ,Halotheo- Halotheo- -Melting mate S01- Diuretic p phylline phylline Point bility, Activity Calculated Found g./100 cc.

Ghlorotheophylline-methyh" 87.4 A 86.4 above 300... 33 f 7 09 amine. Bromotheophylline ethyl- 85.2 82.7 plus d 35 '97 amine. Bromotheophylline n 77.5 77.7 g 30 87 butylamine. V g Bromotheophylline cyclo-' 72. 4' 70.7 298 d 20 g 104 hexylamine. v I Chlorotheophylline cyclo- 68.5 69.0 300p1us d... 102

hexylamine. Bromotheophylline mono- 80.9 77.6 275 plus d..- 22 87 ethanolamine. Bromotheophylline ethyl- 81.2 80.0' 290d 4.1 1 118 enediamine. Chlorotheophylline ethyl- 78.2 78.0 205-23 d 2.6 123 enediamine. i t Bromotheophylline-propyl- 77. 8 76. 2 215 d V 90 enedia e. Bromotheophylline p 65.3 64.0 109-112 1.5 V g 95 methoxy benzylamine. 5' Chlorotheophylline mono- 77. 8 75.6 298 d 12 108 ethanolamine. V Bromotheophylline 61- 83.3 80.6 140-160 d -56 99 v ethylenetriamine. V BromotheophyHine-L3-pro- 71.2 69.3 300d 6 108 panediol. e i BromotheophyIline-2-amino- 167.5 70.6 295d V 116' 2-methy1-1-propanol. Bromotheophylline allyl- 82.0 82.9 295d 2.5 84

amme. Bromotheophylline -benzy1- 70.8 I 68.0 78 60 102 81111119. Bromotheophylline tri- 68.2 79.0 240d 0.5 116 hydroxymethylaminomethane. T Bromotheophylline -p 65.3 g 64.0 109-112 1.5 '95 f methoxy-benzylamine. i

We claim as our-invention: I I 4. Athei'apieutic product;as defined: claim. 1 in? 1. A salt having the following formula: 5 which the primary aminevis a polyalkylehepolyamirie. I

I therapeutic product as {defined claimr 1, O V wh ch the pnmaryamlne lsethylenedrammef '3 g References Cited the fileof'this patent; V V v I UNITED-STATES PATENTS L j wherein Hal is selected from the group consisting of 1,867,332 Shon1e July 12, 19,32", chlorine and bromine and R is a group selected from 2,161,114 IVolWeiler 1939: the group consisting of saturated aliphatic and cyclo- 2,196,495 Greenbaum ,Apr. 9 19.40 aliphatic hydrocarbon groups havingnot morethan' 6 2,404,319 Shelton "11. I u1y '1 6,: 1946 carbon atoms, and Z is a radical selected from the group 7 2,576,106 C usic consisting of H, OH, and NHz. a 1 A 2. A therapeutic product as defined in claim 1,' in OTHER RE R 1 whichthe primary amine is an alkyl monoamine. Beilstein, Vierte Auflage, ol.26, pp.47 3 and'47 6.

3. A therapeutic product as defined inclaimf1, in KattusQe'taL: Bull. Johns Hopkins; Hosp, 89,11 8

which the primary amine is an alkylene diamine. p (1951). 

1. A SALT HAVING THE FOLLOWING FORMULA: 